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2 About The AuthorsThese PowerPoint Lecture Slides were created and prepared by Professor William Tam and his wife, Dr. Phillis Chang.Professor William Tam received his B.Sc. at the University of Hong Kong in 1990 and his Ph.D. at the University of Toronto (Canada) in He was an NSERC postdoctoral fellow at the Imperial College (UK) and at Harvard University (USA). He joined the Department of Chemistry at the University of Guelph (Ontario, Canada) in 1998 and is currently a Full Professor and Associate Chair in the department. Professor Tam has received several awards in research and teaching, and according to Essential Science Indicators, he is currently ranked as the Top 1% most cited Chemists worldwide. He has published four books and over 80 scientific papers in top international journals such as J. Am. Chem. Soc., Angew. Chem., Org. Lett., and J. Org. Chem.Dr. Phillis Chang received her B.Sc. at New York University (USA) in 1994, her M.Sc. and Ph.D. in 1997 and 2001 at the University of Guelph (Canada). She lives in Guelph with her husband, William, and their son, Matthew.

35 Limitations of Friedel–Crafts ReactionsWhen the carbocation formed from an alkyl halide, alkene, or alcohol can rearrange to one or more carbocations that are more stable, it usually does so, and the major products obtained from the reaction are usually those from the more stable carbocations

38 These usually give poor yields in Friedel-Crafts reactionsFriedel–Crafts reactions usually give poor yields when powerful electron-withdrawing groups are present on the aromatic ring or when the ring bears an –NH2, –NHR, or –NR2 group. This applies to both alkylations and acylationsThese usually give poor yields in Friedel-Crafts reactions

39 Does not undergo a Friedel-Crafts reactionThe amino groups, –NH2, –NHR, and –NR2, are changed into powerful electron-withdrawing groups by the Lewis acids used to catalyze Friedel-Crafts reactionsDoes not undergo a Friedel-Crafts reaction

40 Aryl and vinylic halides cannot be used as the halide component because they do not form carbocations readilysp2sp2

51 The ring is more electron rich and reacts faster with an electrophile Z donates electronsY withdraws electronsThe ring is more electron rich and reacts faster with an electrophileThe ring is electron poor and reacts more slowly with an electrophile

52 ReactivitySince electrophilic aromatic substitution is electrophilic in nature, and the r.d.s. is the attack of an electrophile (E) with the benzene p-electrons, an increase in e⊖ density in the benzene ring will increase the reactivity of the aromatic ring towards attack of an electrophile, and result in a faster reaction

53 ReactivityOn the other hand, decrease in e⊖ density in the benzene ring will decrease the reactivity of the aromatic ring towards the attack of an electrophile, and result in a slower reaction

62 If you look at these resonance structures closely, you will notice that for ortho- or para-substitution, each has one resonance form with the positive charge attached to the carbon that directly attached to the substituent Y (o-I and p-II)

63 When Y = EWG, these resonance forms (o-I and p-II) are highly unstable and unfavorable to form, thus not favoring the formation of o- and p- regioisomers, and m- product will form preferentially

64 On the other hand, if Y = EDG, these resonance forms (o-I and p-II) are extra-stable (due to positive mesomeric effect or positive inductive effect of Y) and favorable to form, thus favoring the formation of o- and p- regioisomers

68 11A. Reactivity: The Effect of Electron-Releasing and Electron-Withdrawing GroupsIf G is an electron-releasing group (relative to hydrogen), the reaction occurs faster than the corresponding reaction of benzeneWhen G is electron donating,the reaction is faster

69 If G is an electron-withdrawing group, the reaction is slower than that of benzeneWhen G is electron withdrawing, the reaction is slower

72 Two types of EDGPositive mesomeric effect is usually stronger than positive inductive effect if the atoms directly attacked to the benzene ring is in the same row as carbon in the periodic table

73 Similar to EDG, EWG can withdraw electrons from the benzene ring by resonance effect (negative mesomeric effect) or by negative inductive effectDeactivate the ring by resonance effectDeactivate the ring by negative inductive effect

110 We do not know how to substitute a hydrogen on a benzene ring with a –COOH group. However, side chain oxidation of alkylbenzene could provide the –COOH groupBoth the –COOH group and the NO2 group are meta-directing

113 Which synthetic route is better? Recall “Limitations of Friedel-Crafts Reactions, Section 15.8”Friedel–Crafts reactions usually give poor yields when powerful electron-withdrawing groups are present on the aromatic ring or when the ring bears an –NH2, –NHR, or –NR2 group. This applies to both alkylations and acylationsRoute 2 is a better route

114 Both Br and Et groups are ortho-, para-directingHow to make them meta to each other?Recall: an acyl group is meta-directing and can be reduced to an alkyl group by Clemmensen ketone reduction